Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

J Neuroinflammation. 2012 Jul 2;9:151.

Dimitrije Krstic, Amrita Madhusudan, Jana Doehner, Prisca Vogel, Tina Notter, Claudine Imhof, Abigail Manalastas, Martina Hilfiker, Sandra Pfister, Cornelia Schwerdel, Carsten Riether, Urs Meyer and Irene Knuesel.

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.

 

Abstract

BACKGROUND: Alzheimer’s disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain’s innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease.

METHODS: The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging.

RESULTS: We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas Aβ peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD.

CONCLUSION: Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary Aβ plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.

PMID: 22747753

 

Supplement picture:

Irene Knuesel NRNEURO_Fig1_adapted

 

 

Press release:

Inflammation in the brain leads the way to Alzheimer’s Disease

Research published in Biomed Central’s open access journal Journal of Neuroinflammation suggests that sustained inflammation represents a major risk factor to develop Alzheimer’s disease.

To date it has been difficult to pin down the role of inflammation in Alzheimer’s disease (AD), especially because trials of NSAIDs appeared to have conflicting results. Although the ADAPT (The Alzheimer`s Disease Anti-inflammatory Prevention Trial) was stopped early, recent results suggest that NSAIDs can help people with early stages of AD but that prolonged treatment is necessary to see benefit.

Researchers from the University of Zurich, collaborating with groups at the ETH Zürich and University of Bern, investigated what would be the impact of chronic inflammation, induced by a viral-like infection, on the development of AD in mice. Results showed that in wild-type (genetically nonmodified) mice a single infection before birth (during late gestation) induced long-term changes in AD relevant pathways and significant memory problems at old age.

These mice had increased levels of inflammatory messengers (cytokines), paralleled by a rise in amyloid precursor protein (APP) and its fragments, as well as altered modification and cellular localization of Tau. If this immune system challenge was repeated during aging the effect was exacerbated and resulted in plaque-like aggregation of APP and its fragments; importantly, in the same brain areas that are affected during early stages of AD.

Dr Irene Knuesel who led this research explained, “The AD-like changes within the brains of these wild-type mice occurred without an increase in amyloid β peptides (Aβ). However in mice genetically modified to produce the human version of this aggregation-prone peptide, the viral-like challenge drastically increased Aβ depositions at precisely the sites of inflammation-induced APP depositions. Based on the similarity between these APP/Aβ aggregates and those found in human AD patients, it seems that chronic inflammation due to infection or a disease could be an early triggering event in the development of AD, potentially preceding the formation of typical AD hallmarks for years”. 

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